ABSTRACT Chronic Chagas cardiomyopathy (CCC) is a leading infectious cause of heart failure. CCC emerges in 20- 30% of patients infected with Trypanosoma cruzi, a parasite that is endemic in Latin America. Epidemiologic studies indicate over 7 million Latinos are infected with T. cruzi, including ~300,000 immigrants in the U.S. Infection is transmitted by insect vectors, infected blood donors, and infected pregnant women who transmit the parasite to newborns. CCC emerges after years or decades after quiescent development of progressive ventricular dilatation with diminished systolic performance, conduction system diseases and arrhythmias. CCC is a neglected disease for which there are no effective treatments and due to limited access to cardiac transplantation, most CCC die prematurely. Moreover, the growing burden of T. cruzi infection is predicted to increase the incidence of CCC. This proposal seeks to identify genetic and immune factors that promote CCC and to elucidate how T. cruzi damages the heart. Our studies will capitalize on a collaboration with Dr. A. Pereira and the Brazilian Consortium for Genetics of Chagas Cardiomyopathy, which has amassed clinical data, bio-specimens and explanted CCC hearts from >3,000 subjects. With this extensively revised application we incorporate new Preliminary Results on candidate host and parasite genes that motivate the proposed experiments. Our studies will exploit novel reagents, including a newly constructed and validated capture reagent to sequence T. cruzi exomes from culture, blood and explanted CCC hearts, to identify parasite genetic variants that are enriched in CCC. We propose innovative approaches to assess host immune response in the development of CCC, by comprehensive serologic profiling to identify T. cruzi epitopes that are recognized by host antibodies in patients with and without CCC. We will determine if these antibodies cross react with cardiac proteins. We will also study candidate genes that may promote pathogenesis by perturbing gene expression in iPS cell derived cardiomyocytes and fibroblasts and by in vivo analyses of infected mice. Through parallel studies of fibroblasts and cardiomyocytes we will test if cell-specific responses to T. cruzi contribute to CCC. In addition, we will determine if T. cruzi mutagenesis accounts for resistance to parricidal agents. Together these studies should promote new fundamental knowledge about the mechanisms by which T. cruzi infection perturbs cardiac morphology and function and causes CCC. We aim to: 1) Identify rare genetic variants in humans and parasites that modulate responses to T. cruzi infection and promote CCC; 2) Identify and compare host antibodies in CCC cases and controls to T. cruzi epitopes and cardiac proteins; 3) Compare cardiac transcriptomes in explanted CCC tissues, T. cruzi-infected iPS-CM, genetic and ischemic cardiomyopathies, and unaffected donor hearts; and 4) Analyze cell and mouse models to explore host-pathogen interactions that promote CCC.